The present invention relates to novel cephalosporin antibiotics and prodrugs thereof. It also relates to methods for the synthesis of the compounds and for their use against a broad spectrum of bacteria, including many that are resistant to conventional beta-lactam antibiotics.
The following is provided to aid in the understanding of the present invention. Nothing in this section is to be construed as prior art to the present invention.
Over the past three decades a variety of antibiotics have become available for clinical use. One class of antibiotics that has seen remarkable growth is the cephalosporins, over 70 of which have entered clinical use since 1965.
Unfortunately, the widespread use of antibiotics has resulted in an alarming increase in the number of resistant bacterial strains, especially among clinically important bacterial such as those of the genera Staphylococcus, Salmonella, Enterobacteriaceœ and Pseudomonas, in particular, the species S. aureus and S. pneumoniœ. 
Bacterial resistance to cephalosporins arises primarily by (a) destruction of the antibiotic by xcex2-lactamases; (b) decreased penetration due to changes in bacterial outer membrane composition; and (c) interference with xcex2-lactam binding to penicillin-binding proteins (PBPs). The last mechanism is especially important because the binding of xcex2-lactams to PBPs is an essential step in the inhibition of glycoprotein biosynthesis by this class of antibiotics (glycoprotein being a required bacterial cell-wall component).
Certain gram-positive bacteria are highly resistant to beta-lactam antibiotics such as methicillin-resistant Staphylococcus aureus (MRSA) and various enterococci species. The resistance of MRSA is due to the presence of a PBP known as PBP2a, which binds very poorly to xcex2-lactam antibiotics. Currently, to overcome this resistance, the glycopeptides vancomycin and teicoplanin, which are not dependent on PBP-binding are the antibiotics of choice for treatment of MRSA-induced bacteremia. The quinolone antibacterials and some carbapenems, such as imipenem, also have been reported to be active against a few MRSA strains, but their use is being rapidly limited by the emergence of resistant MRSA strains.
Recent advances in compounds, compositions and methods for treating infections caused by xcex2-lactam antibiotic resistant bacteria are described in commonly owned International Application No. PCT/US95/03976 and U.S. patent applications Ser. Nos. 08/222,262, filed Apr. 1, 1994; 08/369,798, filed Jan. 6, 1995; 08/413,713, 08/413,714, 08/415,065, 08/413,712, 08/415,064, and 08/415,069, all of which were filed on Mar. 29, 1995; 08/455,969, filed May 31, 1995; 08/457,673, filed Jun. 1, 1995; 08/940,508 and 08/937,812, both of which were filed Sep. 29, 1997; 08/730,041, 08/730,039, 08/728,232, 08/430,042, 08/728,233, and 08/730,040, all of which were filed Oct. 11, 1996; and 08/842,915, filed Apr. 17, 1997 and 60/155,496, filed Sep. 22, 1999; all of which are incorporated by reference herein, including any drawings. In addition, International Application No. PCT/WO95/07283, filed Sept. 8, 1994, describes new cephem compounds, and is likewise incorporated by reference herein.
Despite the advances being made in the battle against xcex2-lactam resistant bacteria, there remains a need for newer and better antibiotics to combat the ever-increasing incidence of resistance. The present invention provides such compounds.
The present invention relates to compounds, compositions and methods for treating infections in mammals arising from beta-lactam antibiotic resistant bacteria. Preferred compounds will have a minimum inhibitory concentration (MIC) that is less than the MIC of cefotaxime or imipenem against a beta-lactam resistant organism, in particular a methicillin-resistant Staphylococcal organism. Of course, the compounds of this invention will also be an effective alternative to conventional beta-lactam antibiotics against organisms that are still susceptible to the conventional compounds.
Thus, in one aspect, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, having the chemical structure 
wherein
R1 is selected from the group consisting of 
R2 is selected from the group consisting of hydrogen, CH3xe2x80x94, FCH2xe2x80x94, F2CHxe2x80x94, 
R3 is selected from the group consisting of 
wherein X is selected from the group consisting of hydrogen, halogen, cyano, xe2x80x94NH2, xe2x80x94N(CH3)2, xe2x80x94NHSO2NH2, xe2x80x94SO2NH2 and xe2x80x94SCH3; and,
n is 0 or 1.
An aspect of this invention is compound 1, wherein R1 is selected from the group consisting of 
An aspect of this invention is compound 1, wherein R2 is selected from the group consisting of hydrogen, and 
An aspect of this invention is compound 1, wherein R3 is selected from the group consisting of 
wherein X is selected from the group consisting of hydrogen, halogen, cyano, xe2x80x94NH2, xe2x80x94N(CH3)2, xe2x80x94NHSO2NH2, xe2x80x94SO2NH2 and xe2x80x94SCH3.
An aspect of this invention is compound 1, wherein R1 is selected from the group consisting of 
An aspect of this invention is compound 1, wherein R1 is selected from the group consisting of 
An aspect of this invention is compound 1, wherein R2 is selected from the group consisting of CH3xe2x80x94, FCH2xe2x80x94, F2CHxe2x80x94, 
An aspect of this invention is compound 1, wherein R2 is selected from the group consisting of 
An aspect of this invention is compound 1, wherein R3 is selected from the group consisting of 
wherein X is selected from the group consisting of hydrogen, halogen, cyano, xe2x80x94NH2, xe2x80x94N(CH3)2, xe2x80x94NHSO2NH2, xe2x80x94SO2NH2 and xe2x80x94SCH3.
In the above compound, X is xe2x80x94NH2 in another aspect of this invention.
An aspect of this invention is compound 1, wherein R1 is selected from the group consisting of 
An aspect of this invention is compound 1, wherein R2 is selected from the group consisting of: 
An aspect of this invention is compound 1, wherein 
R2 is hydrogen; and 
wherein X is xe2x80x94NH2.
An aspect of this invention is a compound having structure 1 wherein 
R2 is hydrogen; and 
wherein X is xe2x80x94NH2.
An aspect of this invention is a compound having structure 1 wherein the compound is active against methicillin-resistant Staphylococci, as demonstrated by a lower minimum inhibitory concentration than methicillin against S. aureus Col (MethR)(blaxe2x88x92), S. aureus 76 (MethR)(bla+), S. aureus ATCC 33593 (MethR), S. aureus Spain #356 (MethR), and/or S. haemolyticus 05 (MethR).
An aspect of this invention is a method for treating a methicillin-resistant Staphylococcal infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound having structure 1.
An aspect of this invention is an antibacterial composition comprising a therapeutically effective amount of a compound having structure 1 together with a pharmaceutically acceptable carrier.
An aspect of this invention is the use of the above composition for the treatment of a methicillin-resistant Staphylococcal infection.
An aspect of this invention is a prodrug, or pharmaceutically acceptable salt thereof, having chemical structure 2:
wherein
R1 is selected from the group consisting of 
R2 is selected from the group consisting of hydrogen, CH3xe2x80x94, FCH2xe2x80x94, F2CHxe2x80x94, 
R3 is selected from the group consisting of 
wherein X is selected from the group consisting of hydrogen, halogen, cyano, xe2x80x94NH2, xe2x80x94N(CH3)2, xe2x80x94NHSO2NH2, xe2x80x94SO2NH2 and xe2x80x94SCH3;
R4 is selected from the group consisting of 
R5 is selected from the group consisting of hydrogen and CH3xe2x80x94;
R6 is selected from the group consisting of CH3xe2x80x94, CH3CH2xe2x80x94, CH3CH2CH2xe2x80x94, CH3CH(CH3)xe2x80x94, (CH3)3Cxe2x80x94, CH3Oxe2x80x94, CH3CH2Oxe2x80x94, CH3CH2CH2Oxe2x80x94, CH3CH(CH3)Oxe2x80x94 and (CH3)3COxe2x80x94; and, n is 0 or 1.
An aspect of this invention is prodrug 2, wherein R1 is selected from the group consisting of 
An aspect of this invention is prodrug 2, wherein R2 is selected from the group consisting of
hydrogen, and 
An aspect of this invention is prodrug 2 wherein R3 is selected from the group consisting of 
wherein X is selected from the group consisting of hydrogen, halogen, cyano, xe2x80x94NH2, xe2x80x94N(CH3)2, xe2x80x94NHSO2NH2, xe2x80x94SO2NH2 and xe2x80x94SCH3.
An aspect of this invention is prodrug 2, wherein R1 is selected from the group consisting of 
An aspect of this invention is prodrug 2, wherein R1 is selected from the group consisting of 
An aspect of this invention is prodrug 2, wherein R2 is selected from the group consisting of CH3xe2x80x94, FCH2xe2x80x94, F2CHxe2x80x94, 
An aspect of this invention is prodrug 2, wherein R2 is selected from the group consisting of 
An aspect of this invention is prodrug 2, wherein R3 is selected from the group consisting of 
wherein X is selected from the group consisting of hydrogen, halogen, cyano, xe2x80x94NH2, xe2x80x94N(CH3)2, xe2x80x94NHSO2NH2, xe2x80x94SO2NH2 and xe2x80x94SCH3.
In the above prodrug, X is NH2 in another aspect of this invention.
An aspect of this invention is prodrug 2, wherein 
R2 is hydrogen; and 
wherein X is xe2x80x94NH2.
An aspect of this invention is prodrug 2, wherein 
R2 is hydrogen; and 
wherein X is xe2x80x94NH2.
Pharmaceutically acceptable salts of the above compounds and prodrugs are also an aspect of this invention.
In a pharmaceutically acceptable salt, a compounds herein may be either cationic or anionic and will require an appropriately charged counter-ion. Presently preferred pharmaceutically acceptable salts include (1) inorganic salts such as sodium, potassium, ammonium, chloride, bromide, iodide, nitrate, phosphate or sulfate; (2) carboxylate salts such as acetate, propionate, butyrate, maleate, or fumarate; (3) alkylsulfonate salts such as methanesulfonate, ethanesulfonate, 2-hydroxyethylsulfonate, n-propylsulfonate or isopropylsulfonate; and (4) hydroxycarboxylate salts such as lactate, malate, and citrate. Pharmaceutically acceptable salts wherein the compound or prodrug herein forms the anionic species, usually as the carboxylate anion, are generally prepared by reacting the compound with an organic base, such as, without limitation, benzathene, procain, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine or an inorganic base such as, without limitation, lithium, sodium, potassium, magnesium, calcium, aluminum or zinc hydroxide, alkoxide, carbonate, bicarbonate, sulfate, bisulfate, amide, alkylamide, or dialkylamide.
Another aspect of this invention is a compound or prodrug of this invention, or a salt thereof, that is active against methicillin-resistant staphylococci, as demonstrated by a lower minimum inhibitory concentration than methicillin against S. aureus COL (MethR)(blaxe2x88x92), S. aureus 76 (MethR)(bla+), S. aureus ATCC 33593 (MethR), S. aureus Spain #356 (MethR), and S. haemolyticus 05 (MethR).
An aspect of this invention is a composition comprising a therapeutically effective amount of a compound or prodrug of this invention, or a salt thereof, that may be used to treat infections caused by bacteria resistant to other beta-lactam antibiotics.
An aspect of this invention is a method for treating a infection caused by bacteria resistant to existing beta-lactam antibiotics, in particular methicillin-resistant staphylococci, comprising administering a therapeutically effective amount of a compound or prodrug of this invention, or a salt thereof, to a patient suffering from such b infection.
Of course, the compounds, prodrugs and salts of the present invention may also be used as an alternative treatment for patients infected with bacteria that still are sensitive to current beta-lactam antibiotics.
In another aspect of this invention, the compounds herein may formulated with a pharmaceutically acceptable carrier or diluent for administration to a patient.